Combination antiretroviral therapy (cART) has dramatically shifted the nature of HIV-infection from a terminal illness to a chronic manageable condition, with a life expectancy close to that of the general population. However, infected patients remain at a significantly increased risk of developing HIV-associated neurocognitive disorders (HAND), with 35-70% of all patients (treated and untreated) exhibiting at least subtle impairments in neuropsychological function. This revised R01 proposal from an early-stage investigator (ESI) will examine the neurophysiological bases of HAND, identify markers of HAND progression, and determine how chronic HIV- infection modulates the normal effects of aging on cognitive performance and brain physiology. Over the past two years, my laboratory has evaluated the impact that cART treated HIV-infection has on neural activity and neuropsychological (NP) function through a series of imaging studies using magnetoencephalography (MEG). MEG is a noninvasive and direct measure of neuronal activity with millisecond temporal resolution and good spatial precision (3-5 mm). Using MEG, we have demonstrated neurophysiological abnormalities in the frontal eye fields, dorsolateral prefrontal cortex, and other association cortices, as well as deficits in the primary motor cortex. Most commonly, we have found hyper-activation in association cortices and hypo-activation in primary sensory and motor areas of patients relative to uninfected controls. We have also shown that activation metrics in specific brain areas correlate with scores on NP tests, and that the effects of aging on neuronal activity and cognitive function follow a distinct trajectory in HIV-infected patients compared with controls. Anchored by these extensive preliminary findings, we propose that MEG imaging is uniquely sensitive to the pathophysiology and progression of HAND, and to the additive effects that HIV-infection and aging have on neuronal function. To this end, we will examine 162 adults, 81 HIV-infected patients and 81 demographically-matched controls, divided equally into three age-specific groups (i.e., 22-38, 39-55, and over 55 years). All participants will undergo high- density MEG recording during a series of cognitive tasks, complete several MRI/DTI protocols, and perform a battery of NP assessments that adheres to the recommendations of the Frascati consensus [7]. To evaluate the progression of HAND, a subset of participants (infected and uninfected) will be followed longitudinally at 1.5-year intervals. The Specific Aims of this project are to: (1) Determine the neurophysiological bases of HAND by comparing HIV-infected patients who are impaired, according to the Frascati criteria, to those who are unimpaired; (2) Identify neuronal markers of HAND progression through a short-term longitudinal study of controls and impaired patients, who will undergo repeated MEG and NP testing sessions at 1.5 year intervals; (3) Determine how aging modulates NP function and neuronal activity in patients and controls, and identify the independent effect of HIV-infection on these parameters. We expect that the cognitive and neural deficits associated with HIV-infection will be significantly exacerbated by the aging process in critical brain networks.